Approximately 100,000 Americans suffer from vision loss due to Retinitis Pigmentosa (RP). Despite significant progress in elucidating the molecular genetics of RP over the past three decades, no disease-modifying therapies have been approved. There is compelling evidence implicating endoplasmic reticulum (ER) stress in the pathogenesis of various forms of RP, especially those caused by autosomal dominant protein-folding mutations in Rhodopsin (ADRP). Our team has uncovered key mechanisms whereby the unfolded protein response (UPR), an intracellular signaling pathway activated by ER stress, promotes either cell survival or cell death depending on the severity of the stress. Dominantly inherited Rhodopsin mutations generate high/chronic ER stress to promote photoreceptor cell loss and blindness. We have identified IRE1? as the master unfolded protein response regulator that determines cell fate under ER stress, and have demonstrated that IRE1? inhibitors we call KIRAs (Kinase Inhibitor RNase Attenuators) provide functional cytoprotection to ER stress-challenged photoreceptors. We propose to optimize KIRAs for intravitreal administration and determine photoreceptor cytoprotection efficacy in an acute in vivo model of ER-stress-driven retinal degeneration. This work represents early steps towards developing a new class of agents for RP with disease- modifying potential. The specific Aims of this proposal are: 1: To improve the profile of KIRAs for intraocular administration and efficacy; and, 2: To demonstrate optimized KIRAs boost efficacy in an ER stress model of rodent RP.